A MODEL OF ATRIAL FIBRILATION TRIGGERS

描述（由申请人提供）：心房颤动（AF）是最常见的需要医疗干预的心律失常，仅在美国就影响了200万人，每年花费超过60亿美元。房颤导致中风风险增加3-5倍，死亡风险增加1.9倍。目前的治疗方法并不完全有效，因为人们对房颤的发病机制知之甚少。最近的证据表明，肺静脉（PV）的异常电活动引发了某些类型的房颤。最近，我们在成年小鼠中发现了一种以前未被识别的细胞群，这种细胞群局限于肺静脉和心房的部分区域。这些细胞表达黑素细胞标记物，包括多巴胺自变酶（Dct），并具有电兴奋性，产生类似心房肌细胞记录的动作电位。我们将这些细胞称为“心脏黑色素细胞样细胞”（CMLCs）。在缺乏Dct蛋白的小鼠（Dct-/-）中进行的实验显示，与对照组相比，自发性和诱发性心房心律失常增加。重要的是，尽管Dct-/-心脏结构正常，Dct-/-小鼠具有与Dct小鼠相似的心房有效不应期，但Dct-/- CMLC动作电位延长。此外，早期去极化（EADs）在Dct-/- CMLCs中普遍存在，但在Dct-/-心房肌细胞中并不存在，这表明CMLCs在Dct-/-动物中明显增加的心律失常发生中起着关键作用。本提案中包含的实验旨在：1：表征CMLCs中动作电位复极化的离子电导率。确定Dct-/- CMLCs中动作电位延长的离子决定因素。了解CMLCs在调节心脏兴奋性中的作用可能最终导致新的房颤治疗策略的发展。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia requiring medical intervention, affecting 2 million people in the United States alone and costing over $6 billion dollars annually. AF results in a 3-5 fold increased stroke risk and a 1.9 fold increased risk of death. Current therapies are incompletely effective, because mechanisms initiating AF are poorly understood. Recent evidence demonstrates abnormal electrical activity from pulmonary veins (PV) initiates some types of AF. Recently, we identified a previously unrecognized cell population in the adult mouse that is confined to the pulmonary veins and portions of the atria. These cells express melanocyte markers, including Dopachrome Tautomerase (Dct), and are electrically excitable, generating action potentials that resemble those recorded in atrial myocytes. We refer to these cells as "cardiac melanocyte-like cells" (CMLCs). Experiments in mice (Dct-/-) lacking the Dct protein, show increased spontaneous and induced atrial arrhythmia when compared to control Dct littermates. Importantly, although Dct-/- hearts are structurally normal and Dct-/- mice have atrial effective refractory periods similar to Dct mice, Dct-/- CMLC action potentials are prolonged. Furthermore, early after-depolarizations (EADs) are prevalent in Dct-/- CMLCs, but not in Dct-/- atrial myocytes, suggesting a critical role for CMLCs in the increased arrhythmogenesis evident in Dct-/- animals. Experiments contained in this proposal are designed to: 1: Characterize the ionic conductances underlying action potential repolarization in CMLCs. 2: Identify the ionic determinants of action potential prolongation in Dct-/- CMLCs. Insights into the roles of CMLCs in regulating cardiac excitability may ultimately result in insights that could lead to the development of novel therapeutic AF treatment strategies. PUBLIC HEALTH RELEVANCE: This project will build upon previous work describing an animal model of atrial arrhythmias. Further work is expected to result in identifying potential new drug targets to for atrial fibrillation treatment.